Anxiety is the most common psychiatric disorder. Anxiety is associated with increased risk of cardiovascular events, independent of conventional risk factors. However, the mechanisms underiying this link are unknown, and it has never been proved that treating anxiety reduces cardiovascular risk. This project will address these important issues. We have gathered compelling data demonstrating that even modest anxiety symptoms are associated with sympathetic nerve activation, inflammation, and profound impairment of resistance vessel function in humans. Using a multidisciplinary approach, we will address three speciflc aims: 1) Does anxietv produce vascular dvsfunction through increased inflammation or oxidant stress? We will measure ex vivo endothelial cell proteins reflecting inflammation and oxidant stress in subjects with anxiety symptom scores in the highest and lowest quartiles. We will then test whether anti-inflammatory (salsalate) and anti-oxidant (ascorbic acid) interventions reverse vascular dysfunction in high compared to low anxiety subjects. This aim will additionally examine whether peripheral resistance vessel dysfunction is also present in the brain using functional MRI to measure cerebral blood flow, and whether this is improved by salsalate. 2) Does anxietv produce vascular dysfunction through svmpathetic activation? We will test whether sympathetic inhibition with clonidine for 4 weeks improves inflammation, oxidant stress and vascular dysfunction to a greater degree in high than low anxiety subjects. 3) Does treatment of anxietv improve svmpathetic activation, inflammation, oxidant stress and Vascular dvsfunction? We will randomly assign subjects with high anxiety to a novel mindfulness-based acceptance and commitment therapy (ACT) or time control. This therapy has been shown in our hands and others to have substantial and durable effects on anxiety symptoms. We will test whether ACT produces signiflcantly greater improvements in microneurographic sympathetic nerve activity, endothelial cell proteins reflecting inflammation and oxidant stress, and forearm resistance vessel function. This project should: A) Provide compelling evidence that anxiety causes vascular damage. B) Elucidate mechanisms involved in the effects of anxiety on the vasculature. C) Help develop novel phenotypes for future research on anxiety classiflcation, severity and treatment. D) Suggest new strategies for cardiovascular risk stratiflcation and prevention. We will achieve these goals through a distinctive multidisciplinary collaboration between investigators expert in cardiovascular biology, psychiatry, behavioral psychology and neuroimaging.